Standard supportive care bested either HC alone or combined with azithromycin

The much-touted hydroxychloroquine (HC) for treatment of patients with Covid-19, combined with or without azithromycin (AZ), not only may not help mitigate the virus’ effect, it also may increase overall mortality, according to finding from a retrospective analysis conducted by the U.S. Veterans Health Administration.

Moreover, in its treatment guidelines for Covid-19, the National Institutes of Health underscored the fact that there is not enough data for the use of chloroquine or hydroxychloroquine and noted: “If chloroquine or hydroxychloroquine is used, clinicians should monitor the patient for adverse effects, especially prolonged QTc interval.”

The HC-AZ combo was elevated to the limelight on April 5, when President Donald Trump spoke enthusiastically about it as a treatment for Covid-19, adding that the U.S. has stockpiled 29 million pills and that the FDA “feels good about it.”

“What do you have to lose? And a lot of people are saying that when — and are taking it — if you’re a doctor, a nurse, a first responder, a medical person going into hospitals, they say taking it before the fact is good,” Trump said. “But what do you have to lose?”

If the findings of this new analysis are borne out by RCT data, the answer to the president’s question would be: “Your life.”

The VA analysis, published before peer review on medRxiv, analyzed 368 patients in the VA health system with SARS-CoV-2 who were treated with standard supportive management with the addition of either HC alone (n=97), HC plus AZ (n=113), or no HC (n=158). The primary endpoints of their analysis were the need for mechanical ventilation or death.

“Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively,” Jayakrishna Ambati, MD, and colleagues wrote. “Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively.”

They also found that the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03), but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72).

Ventilation risk was similar in both groups — HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group.

There were 70 deaths among the 368 patients evaluated, with the lowest rate of death among those not treated with HC (n=18), compared with 27 deaths in the HC alone arm and 25 deaths in the HC+AZ arm.

Those not on the drug regimens also fared better for discharge with 140 or 88.6% of those only on standard supportive management going home, compared with 70 (72.2%) in the HC arm and 88 (77.9%) in the combination arm.

The study authors noted that patients with more severe disease were more likely to be prescribed either HC alone or in combination with AZ.

The patients in all arms of the study were around age 70, more than half were black, and all had a BMI around 30 kg/m2.

“Thus, as expected, increased mortality was observed in patients treated with hydroxychloroquine, both with and without azithromycin,” they wrote. “Nevertheless, the increased risk of overall mortality in the hydroxychloroquine-only group persisted after adjusting for the propensity of being treated with the drug. That there was no increased risk of ventilation in the hydroxychloroquine-only group suggests that mortality in this group might be attributable to drug effects on or dysfunction in non-respiratory vital organ systems. Indeed, hydroxychloroquine use in Covid-19 patients has been associated with cardiac toxicity.”

Ambati and colleagues noted that in vitro hydroxychloroquine was shown to have a 50% maximal effective concentration (EC50) with a range of 4.5 μM to 17μM against SARS-CoV-2. The drug is approved for use in rheumatoid arthritis and lupus with dosing regimens that produce much lower peak serum drug concentrations (~1μM). “Administering higher doses of hydroxychloroquine to achieve presumed antiviral concentrations might increase the risk of adverse events,” the study authors wrote. “Interestingly, a randomized, controlled trial of high-dose chloroquine, the parent compound of hydroxychloroquine that also has been reported to have in vitro antiviral activity against SARS-CoV-2 and similar peak serum concentrations in humans, was halted prematurely due to cardiac toxicity and higher fatality rates in the high-dose chloroquine-treated Covid-19 patients.”

Limitations of the study include its design, and even though they used propensity score adjustment for relevant confounders, selection bias could not be ruled out. Also, since the trial was comprised of mostly men over age 65, the results may not be generalizable to younger men, women, or children.

Nonetheless, they concluded: “These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.”

  1. Hydroxychloroquine (HC) for treatment of patients with Covid-19 combined with or without azithromycin (AZ) not only does not help mitigate the virus’ effect, it increased overall mortality.

  2. Be aware that this retrospective analysis was published before peer review.

Candace Hoffmann, Managing Editor, BreakingMED™

The study was supported by the NIH and the DuPont Guerry, III, Professorship, and University of Virginia Strategic Investment Fund to Ambati.

Ambati is a co-founder of iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and has received consultancy fees from Allergan, Biogen, Boehringer Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences, all unrelated to this work. He is also named as an inventor on a patent application filed by the University of Virginia relating to Covid-19 but unrelated to this work.

Cat ID: 125

Topic ID: 79,125,730,933,125,190,520,926,192,927,151,928